CHF is a major health problem affecting over 23 million people worldwide causing significant morbidity and mortality1. CHF occurs when the heart inadequately pumps oxygenated blood to the rest of the body, resulting in the retention of fluid (oedema), shortness of breath (dyspnea) and lethargy. Often, it is also accompanied by renal failure as the kidneys strain to maintain glomerular filtration in an attempt to excrete the build up of excess fluids2. CHF may be caused by one or a combination of factors including: weakened heart muscle, damaged heart valves, blocked blood vessels supplying the heart muscle (ie cardiac arteries), high blood pressure leading to a thickening of the heart muscle (ie left ventricular hypertrophy), congenital heart disease, prolonged arrhythmias, infections, and life style factors such as smoking, obesity and alcohol or drug (eg cocaine) consumption which can, for example, be the cause of long term, uncontrolled high blood pressure (hypertension) that may damage the heart muscle and blood vessels. If steps are not taken to treat CHF when it becomes apparent and/or modify patient life style, the CHF may become a long term (ie chronic) condition. The severity of symptoms of patients with chronic CHF can progress to a level where there is a “marked limitation in activity [and the patient is] comfortable only at rest” as per Class III of the New York Heart Association (NYHA) CHF functional classification. Consequently, patients with chronic CHF that has progressed to NYHA class III can require frequent hospitalisation and/or palliative care. Moreover, while such chronic CHF is generally stable, it may easily decompensate to the often critical state known as acute decompensated congestive heart failure (ADCHF). This can be caused for a variety of reasons including arrhythmias, ischaemia, illness such as pneumonia and poor compliance with diet and medications19.
In the United States alone, over 1.1 million people are admitted to hospital every year with ADCHF1, 10% of which die in care and 40% of which die within the year. Further, it has been reported that over 6.5 million days of hospitalisation per year in the United States are attributable to ADCHF3. These costs account for almost 50% of the US$34 billion spent each year on heart failure care in the United States. Unfortunately, ADCHF remains as an unmet clinical need, with current monotherapeutic and polytherapeutic treatments being effectively, and efficaciously, limited at alleviating symptoms only.
Vessel dilator (VSDL) is a naturally occurring 37 amino acid (aa) cardiac peptide consisting of amino acids 31-67 of the 126 aa atrial natriuretic peptide (ANP) prohormone4, 6 and 7. Like other natriuretic peptides, the main biological activity of VSDL is to regulate blood pressure and maintain plasma volume in healthy individuals by mediating natriuretic, diuretic and haemodynamic effects4. Preliminary studies on VSDL's effect in CHF have been conducted via both preclinical and human clinical studies8, 9. One of the first studies exploring the use of synthetic VSDL in a CHF animal model was in normal and compensated aorto-caval (AV) fistula dogs, resulting in similar significant reductions in arterial blood pressure, right atrial pressure and elevations in urinary sodium excretion5. The human studies have involved patients with chronic, but stable, New York Heart Association (NYHA) Class III CHF10, and have shown that VSDL can significantly improve natriuretic, diuretic and haemodynamic parameters without any symptomatic side effects. In particular, it has been shown that VSDL is able to increase urine flow 2- to 13-fold, and urine flow was still increased (P<0.001) 3 hours after the VSDL infusion was halted10. Further, it was found that VSDL enhanced sodium excretion 3- to 4-fold in CHF patients (P<0.01), and was still significantly (P<0.01) elevated 3 hours after infusion. Moreover, it was found that VSDL could: decrease systemic vascular resistance (SVR) (24%); decrease pulmonary vascular resistance (PVR) (25%); decrease pulmonary capillary wedge pressure (PCWP) (33%); decrease central venous pressure (CVP) (27%); increase cardiac output (CO) (34%); increase cardiac index (CI) (35%); and increase stroke volume index (SVI) (24%); without significantly affecting heart rate or pulmonary artery pressure in the CHF patients. In addition, it is also known that VSDL promotes the synthesis of the renal protective agent, prostaglandin E2 (PGE2), and can increase circulating PGE2 8-fold compared to basal levels11. PGE2 also benefits CHF patients by decreasing mean arterial pressure and total peripheral resistance while increasing stroke volume index and cardiac output.
It has been reported that VSDL circulates in healthy humans at significantly higher basal levels than other atrial natriuretic peptides, including ANP and B-type natriuretic peptide (BNP), where the circulating concentration of VSDL is 17-fold and 48-fold higher than ANP and BNP respectively. Hitherto the studies described herein, this was believed to owe, in part, to VSDL possessing a significantly longer circulatory t1/2 of ˜120 minutes and biological t1/2 of ˜>6 hours. In comparison, it has been reported that BNP has a circulating t1/2 of ˜3.1 minutes and biological t1/2 of ˜<½ hour4, 6-9, 12 and 13. In patients with volume overload, including those with CHF, circulating natriuretic peptides are elevated. This is thought to be indicative of a compensatory mechanism attempting to reinstate homeostasis. However, in severe congestion, it appears that the body is unable to produce sufficient quantities to restore balance.
The present applicant has now recognised that the benefits demonstrated in preclinical and clinical use of VDSL in the treatment of CHF are superior to those seen with the current natriuretic treatments for ADCHF14, and hereby proposes VSDL administration to patients with chronic CHF or ADCHF as a safe and effective treatment for mediating beneficial haemodynamic effects with additional beneficial natriuretic, diuretic and renal effects, whilst regulating plasma volume and blood pressure (BP) within clinically acceptable ranges and without seriously adverse side effects. It is also anticipated that such VSDL treatment may reduce hospitalisation time and readmission rates for chronic CHF and ADCHF patients. Further, the present applicant has found that effective treatment of chronic CHF and ADCHF patients with VSDL can be achieved with doses that are substantially lower than expected.